Aripiprazole, Dopamine, and Well-Being - Science or Selling Point?

Suppose you were a drug company, and you've invented a new drug. It's OK, but it's no better than the competition. How do you convince people to buy it?

You need a selling point - something that sets your product apart. Fortunately, with drugs, you have plenty of options. You could look into the pharmacology - the chemistry of how your drug works in the body - and find something unique there. Then, all you need to do is to spin a nice story to explain how the pharmacological properties of your drug make it brilliant.On an entirely unrelated note, aripiprazole (Abilify) is an antipsychotic marketed in the US by Bristol Meyers-Squibb. A Cochrane meta-analysis finds that it's about as good as any other antipsychotic in terms of efficacy and side effects. As good, but no better. However, uniquely, aripiprazole is a D2 receptor partial agonist. Other antipsychotics work by blocking D2 receptors in the brain, switching them off (full antagonism). Aripiprazole also blocks D2 receptors, but it activates them slightly in the process (partial agonism).

Is that a good thing? A paper just published says yes - The relationship between subjective well-being and dopamine D2 receptors in patients treated with a dopamine partial agonist and full antagonist antipsychotics. The research in question was funded, by the way, by Bristol Meyers-Squibb. Let's see if it holds up.

The authors got 22 patients with schizophrenia who were taking an established antipsychotic, either olanzapine or risperidone. These are both D2 antagonists. Incidentally, neither of them is made by Bristol Meyers-Squibb. 11 of the patients were switched to aripiprazole, while 11 stayed on their original drug. There was no blinding, and no randomization. (The dose of aripiprazole was randomized, although still unblinded, but the assignment to aripiprazole itself wasn't).
Lo and behold, the patients who switched reported improved "well-being". Because there was no randomization and no blinding, and because the outcome was entirely subjective, this could be entirely explained as a placebo effect (or an experimental demand effect.) Especially when you consider that the patients were most likely convinced to take part in the study by being told that aripiprazole would make them feel better than their original drug.

That's not all, though. They also did some brain scanning, using PET to measure D2 receptor occupancy. On average aripiprazole blocked more D2 receptors than the other antipsychotics, which is what you'd expect, as it has a very high affinity for that receptor. But it's a partial agonist, remember - it binds to D2 receptors without switching them "off" entirely.

The paper suggests that this is a good thing because it doesn't make people feel horrible, which is what normally happens when you block almost all of someone's D2 receptors (they're rather important). By switching on the receptors as well as blocking them, it makes you feel OK.
Nice story, and scientifically it's not unreasonable. And as you can see on this plot, in the non-aripiprazole patients (triangles), D2 occupancy in the ventral striatum was negatively correlated with well-being, but in the aripiprazole patients (circles), it wasn't.

Great - except that the range of D2 occupancies in the aripiprazole group is so narrow that no correlation would be apparent even if there was one. The occupancies in the aripiprazole group are all extremely high, 80-95%. There's just no room for a correlation to appear. (Think about it this way - in children, age is strongly correlated with height, but if you only looked at a bunch of 7 year olds, you wouldn't know that.) This is high-school statistics.

This scatter-plot is in fact exactly what you'd expect assuming that a) aripiprazole strongly blocks D2 receptors, and makes people feel awful, just like any other strong D2 blocker and b) the placebo effect made some of the aripiprazole group feel (or at least say that they feel) a bit better than they otherwise would.

You'll note also that the aripiprazole group reported feeling no better than the other antipsychotic group, and that the single most miserable patient was on aripiprazole. The paper concludes on an optimistic note -

The present data suggests that aripiprazole may be associated with early and sustained improvement in subjective well-being, notwithstanding the very high D2 occupancy. This may be related to its partial agonist profile at D2 receptors.

I leave it to the reader to evaluate this claim, and to consider how likely we are to progress in our understanding of the brain when so much of the research is funded by organisations with a direct financial interest in certain theories.

[BPSDB]

Mizrahi, R., Mamo, D., Rusjan, P., Graff, A., Houle, S., & Kapur, S. (2009). The relationship between subjective well-being and dopamine D2 receptors in patients treated with a dopamine partial agonist and full antagonist antipsychotics The International Journal of Neuropsychopharmacology, 12 (05) DOI: 10.1017/S1461145709000327